Topiramate and darbepoetin alpha ameliorate bilirubin-induced neuronal cell damage.

OBJECTIVE: The aim of this study was to determine whether prophylactic darbepoetin alpha and/or topiramate administration could prevent bilirubin neurotoxicity (BNTx) in experimental model of kernicterus. MATERIALS AND METHODS: A total of 60 Wistar albino rat puppies with experimental kernicterus model were included in the study. The Kernicterus was established administering a bilirubin injection via a cisterna magna puncture 30 minutes after ip drug injection. The puppies were divided into five groups with 12 in each group as shown below: a control group, bilirubin group, darbepoetin alpha group, topiramate group and darbepoetin alpha+ topiramate group. Darbepoetin alpha and/or topiramate were administered on day 5 intraperitoneally (ip). At the 6th and 24th hours, bilirubin induced neurological dysfunction (BIND) score was used to assess behavioral changes. Hearing functions were evaluated on days 10 and 28. On day 30, the Water Maze water tank test was implemented to evaluate spatial memory. The rats were sacrificed on days 6 and 34 and apoptosis in the globus pallidus and hippocampus was examined. RESULTS: The BIND score was improved following darbepoetin alpha treatment. Neither darbepoetin alpha nor topiramate therapy ameliorate spatial memory. There were no significant differences between groups in terms of the auditory brainstem response (ABR). The combined use of darbepoetin alpha and topiramate lead to slight decrease in apoptosis. CONCLUSIONS: Darbepoetin alpha or topiramate administration ameliorates bilirubin induced neurological dysfunction in experimental model of kernicterus.

TRAIL-Dependent Resolution of Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease characterized by the persistence of activated myofibroblasts resulting in excessive deposition of extracellular matrix proteins and profound tissue remodeling. In the present study, the expression of tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) was key to the resolution of bleomycin-induced pulmonary fibrosis. Both in vivo and in vitro studies demonstrated that Gr-1+TRAIL+ bone marrow-derived myeloid cells blocked the activation of lung myofibroblasts. Although soluble TRAIL was increased in plasma from IPF patients, the presence of TRAIL+ myeloid cells was markedly reduced in IPF lung biopsies, and primary lung fibroblasts from this patient group expressed little of the TRAIL receptor-2 (DR5) when compared with appropriate normal samples. IL-13 was a potent inhibitor of DR5 expression in normal fibroblasts. Together, these results identified TRAIL+ myeloid cells as a critical mechanism in the resolution of pulmonary fibrosis, and strategies directed at promoting its function might have therapeutic potential in IPF.

Comparison of the effect of propofol and sevoflurane anaesthesia on acute and chronic postoperative pain after hysterectomy.

There is some evidence that propofol may reduce acute postoperative pain; however, the results are inconsistent. Furthermore, there is a paucity of information about the type of anaesthesia and chronic pain. This study was designed to evaluate the hypothesis that propofol reduces acute and chronic postoperative pain compared with sevoflurane. In a randomised, prospective, double-blind trial, we assigned 80 patients having open total abdominal hysterectomy surgery to anaesthesia with either sevoflurane or propofol. Anaesthesia was titrated to clinical needs and bispectral index values to between 40 and 60. Postoperative pain was managed with pethidine and diclofenac. Acute postoperative pain for 24 hours and chronic postoperative pain at one and three months after surgery were evaluated. The Hospital Anxiety and Depression Scale was used to evaluate patient anxiety and depression after one and three months. There were no significant differences between the groups for opioid consumption or opioid-induced side-effects. Pain scores in the first four hours were significantly higher in the sevoflurane group. Persistent surgical pain was observed less frequently (7 out of 40 patients in the propofol group and 21 out of 40 in the sevoflurane group at three months post-surgery, P <0.01) and pain scores were lower at one and three months in the propofol group (0.78±0.55 versus 2.23±0.73 for the sevoflurane group at three months post-surgery, P <0.01). Anxiety and depression scores were significantly lower in the propofol group at three months. In this study, general anaesthesia with propofol was associated with reduced early acute postoperative and persistent pain, compared to sevoflurane-based anaesthesia, among patients undergoing open abdominal hysterectomy.

Effect of vitamin B12 deficiency on otoacoustic emissions.

The aim of this study was to investigate the possible association between otoacoustic emission (OAE) values and cochlear function in patients with vitamin B12 deficiency and no evidence of symptomatic hearing loss. Two groups were studied: Group 1: patients with vitamin B12 deficiency; Group 2: a matched control group of patients with normal vitamin B12 levels. There was no evidence of symptomatic hearing loss in either group. Transiently evoked OAEs (TEOAEs) and spontaneous OAEs (SOAEs) were recorded. A comparative analysis of the studied parameters revealed that results at TEOAE 1000, SOAEs 1500 and SOAEs 4000 Hz were somewhat lower in the vitamin B12 deficient group compared with the control group. According to our findings, there was a significant association between vitamin B12 deficiency and cochlear dysfunction. We recommend that routine vitamin B12 serum levels be determined when evaluating patients for symptomatic hearing loss.

Comparison of pre-emptive tonsillar lodge infiltration with ropivacaine versus intravenous tramadol in pediatric tonsillectomies: a randomized placebo-controlled study.

OBJECTIVE: To investigate the placebo controlled effect of pre-emptive local infiltration of ropivacaine and intravenous tramadol in postoperative pain and nausea-vomiting in pediatric tonsillectomy cases. METHODS: 90 children at ASA I-II physical status, who are between 2 and 9 years old, underwent tonsillectomy were included to the study. Patients were randomized into one of three study groups. Group I was i.v. saline group (placebo group), Group II was preemptive 1.5 ml 0.75% ropivakain to the tonsil lodge and Group III was preemptive 1mg/kg i.v. tramadol. Hemodynamic parameters and synchronized Maunuksela pain scores were evaluated in the post anesthetic care unit. RESULTS: There was no difference in age, weight, sex and hemodynamic parameters of children included to the study groups. Postoperative nausea vomiting was significantly lower in Group II and pain scores at resting and swallowing are significantly lower than the other study groups. Maunuksela pain scores at 2nd, 3rd, 6th and 9th hours while resting were significantly lower in Group II compared with Groups I and III (p<0.001). The comparison of scores between groups I and III were similar. Maunuksela pain scores during swallowing were significantly lower in Group II compared with Group I and III at 2nd, 3rd, 6th, 9th, 12th, 21st and 24th hours postoperatively (p<0.001). While comparing Maunuksela pain scores of Groups I and III, significantly lower scores are determined at 2nd and 24th hours in Group III (p<0.001). Analgesic needs were significantly low in Group II at postoperative period (150 ± 30 mg paracetamol) (p<0.05). It was similar in Groups I and III (Group I: 400 ± 40 mg, Group III: 360 ± 40 mg paracetamol). CONCLUSION: This study showed that peritonsillar ropivacaine infiltration might produce an effective postoperative analgesia probably due to a preventing effect on sensitization of the pain pathways.

Determining the optimal fentanyl dose for dilation and curettage procedures.

AIM: This study attempted to determine an optimal dose of fentanyl, a drug frequently used in dilation and curettage (D&C) procedures, which is commonly performed as a brief outpatient intervention. METHODS: The optimal fentanyl dose was determined using Dixon's up-and-down method. The study was accomplished with a beginning fentanyl dose of 1 microg kg(-1) with a step size of 0.1 microg kg(-1) fentanyl. RESULTS: The ED50 [95% confidence interval (CI)] for fentanyl for successful anesthesia in D&C procedures was found to be 0.45 (0.35-0.55) microg kg(-1) and the ED95 value was 0.50 (0.45-0.60) microg kg(-1). CONCLUSION: This dose is considerably lower than the standard dose that is used at present, which is 1 microg kg(-1). To the best of our knowledge, the current study is the first to show that a significantly reduced dose of fentanyl can be as effective as higher doses in D&C procedures using Dixon's up-and-down method.

The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A.

TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus-induced and house dust mite antigen-induced (HDM antigen-induced) chronic asthma. Tlr6-/- mice with fungal- or HDM antigen-induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6-/- versus WT asthmatic mice. Tlr6-/- DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6-/- mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic Tlr6-/- mice restored IL-17A production and substantially reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with that in untreated asthmatic Tlr6-/- mice. Together, our data demonstrate that TLR6 activation is critical for IL-23 production and Th17 responses, which both regulate the allergic inflammatory response in chronic fungal-induced asthma. Thus, therapeutics targeting TLR6 activity might prove efficacious in the treatment of clinical asthma.

Targeting ST2L potentiates CpG-mediated therapeutic effects in a chronic fungal asthma model.

IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.

Effects of cytokines on mechanical and epithelial bioelectric responses to methacholine and hyperosmolarity in guinea-pig airways: an in vitro study.

We observed previously that lipopolysaccharide (LPS) 18 h after i.p. injection of guinea pigs increased transepithelial potential difference (V(t)), hyperpolarization responses to methacholine, and hyperosmolarity-induced, epithelium-derived relaxing factor (EpDRF)-mediated relaxation responses, in excised and perfused tracheal segments. To investigate their roles in these changes, the effects of cytokines on in vitro epithelial bioelectric and smooth muscle mechanical responses were investigated using the isolated, perfused trachea preparation. Tracheas were incubated (6 h) with LPS or IL-1beta, IL-4, IL-13, IFN-gamma, TNF-alpha, singly or in combination. Incubation with LPS and cytomix (IL-1beta+IFN-gamma+TNF-alpha together) had no effect on muscle reactivity to methacholine, but potentiated D-mannitol-induced relaxation. Individually, IL-1beta and IFN-gamma inhibited methacholine-induced contractions and potentiated D-mannitol-induced relaxation responses. TNF-alpha increased contractions to methacholine but had no effect on relaxation responses to D-mannitol. Methacholine elicited hyperpolarization in low concentrations and depolarization in high concentrations. The individual cytokines decreased the hyperpolarization response to low methacholine concentrations and increased the depolarization response to high methacholine concentrations but had no effect on V(t) responses to D-mannitol. Cytomix did not affect V(t) responses to methacholine, but potentiated both the hyperpolarization and depolarization responses to D-mannitol. In Ussing chambers all agents except IL-1beta and IFN-gamma increased V(t); IL-1beta decreased slightly but none of the other agents affected transepithelial resistance (R(t)). The results indicate that cytokines and LPS alter smooth muscle reactivity to methacholine, potentiate EpDRF-mediated relaxation responses and, thereby, mimic the effects of LPS treatment in vivo, but do not recapitulate LPS' effects on V(t) responses.

The analgesic effect of lornoxicam when added to lidocaine for intravenous regional anaesthesia.

BACKGROUND: The aim of the study was to evaluate the effect of lornoxicam (L) on sensory and motor block onset time, tourniquet pain, and postoperative analgesia, when added to lidocaine in intravenous regional anaesthesia (IVRA). METHODS: Forty-five patients undergoing hand surgery were randomly and blindly divided into three groups as to receive either i.v. saline and IVRA with lidocaine 0.5% (Control group, n=15), i.v. saline and IVRA lidocaine 0.5% with lornoxicam (L-IVRA group, n=15), or intravenous lornoxicam and IVRA lidocaine 0.5% (L-IV group, n=15). Sensory and motor blocks onset time, and tourniquet pain was measured after tourniquet application at 5, 10, 20, and 30 min, and analgesic use were recorded during operation. After the tourniquet deflation, at 1, 30 min, and 2, 4 h, visual analogue scales score, the time to first analgesic requirement, total analgesic consumption in first 24 h, and side effects were noted. RESULTS: Sensory and motor block onset times were shorter and the recovery time prolonged in the Group L-IVRA compared with the other group (P=0.001). A decreased tourniquet pain, a prolonged time first analgesic requirement [229 (85) min vs 28 (20) and 95 (24) min, P=0.0038) and less postoperative analgesic requirements during 24 h were found in Group L-IVRA compared with the other groups (P<0.05). CONCLUSIONS: The addition of lornoxicam to lidocaine for intravenous regional anaesthesia shortens the onset of sensory and motor block, decreases tourniquet pain and improves postoperative analgesia without causing any side effect.

Neurotoxicity with single dose intrathecal midazolam administration.

BACKGROUND AND OBJECTIVE: The aim of study was to investigate the electron microscopic changes in the medulla of the spinal cord that occur with intrathecal midazolam administration. METHODS: Twenty-eight albino rabbits of New Zealand type were randomized into two groups. Following anaesthesia, 16 rabbits were given 300 microg of midazolam (Group M) and 12 rabbits were given 0.3 mL of normal saline solution (Group C) intrathecally. Eight rabbits from Group M (Group M1) and 6 rabbits from Group C (Group C1) were sacrificed 24 h after the anaesthesia and 8 rabbits from Group M (Group M2) and 6 rabbits from Group C (Group C2) were sacrificed 6 days after the anaesthesia. The lumbosacral portion was removed by laminectomy and thin sections were examined microscopically. RESULTS: Severe separation in myelin lamella of the large axons, honeycomb appearance, slight separation in myelin lamella of small to moderately large axons, degenerate vacuoles in the cytoplasm and nuclear membrane irregularity were observed in neurons of Groups M1 and M2. Myelin lamella and nuclear membranes were found to be regular, vacuoles and oedema were observed in the neurons in the Groups C1 and C2. CONCLUSION: Midazolam administered at single dose by the intrathecal route may have neurotoxic effects on the neurons and myelinated axons at 24 h and 6 days following administration.

Complete relief of pain in acute painful diabetic neuropathy of rapid glycaemic control (insulin neuritis) with venlafaxine HCL.

This article reports a case of a diabetic patient who suffered from acute painful diabetic neuropathy, following an intensive insulin treatment after a poor glycaemic control period of 8 yr. On the 15th day of the insulin treatment, which enabled rapid successful glycaemic control, the patient began complaining of pain and a burning sensation in the lower extremities, especially during the night. Venlafaxine HCL was initiated and the patient was completely free of pain on the third day of the treatment. As insulin neuritis is infrequent among diabetic patients we consider it is worth reporting the dramatic effect of the venlafaxine HCL treatment.

Early changes in parameters of bone and mineral metabolism during therapy for hyper- and hypothyroidism.

The effects of thyroid hormones on various organs and metabolic systems have been the focus of intensive research. In this study we investigated the mechanisms of the changes in some parameters of bone and mineral metabolism before and during treatment of hyper- and hypothyroidism. Our study groups were as follows; 1) Untreated hyperthyroid patients (n= 38), 2) Hyperthyroid patients treated for three months (n=21), 3) Untreated hypothyroid patients (n=27), 4) Hypothyroid patients treated for three months (n= 20), and 5) Euthyroid control subjects (age, weight, sex and menopausal status matched) (n = 47). As expected, the mean serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and urinary Ca/creatinine and deoxypyridinoline (D-Pyr)/creatinine levels were higher in group-1 than in the control group. Serum PTH level was lower in group-1 than in group-5. However, after treatment for three months (group-2) we found that the serum and urinary levels of these parameters (except ALP) were not different than in the control group. Group-3 and group-4 did not show any differences in these parameters compared with group-5. Covariance analysis showed that urinary D-Pyr excretion had a positive, independent relationship to the serum free T3 level and age (P < 0.001 and P = 0.02, respectively). These results suggest that both bone formation and resorption markers increase in hyperthyroid patients, and with the treatment, particularly, in the period of first three months the bone resorption markers decrease rapidly. If the treatment is maintained the decrease slows, becoming more gradual. However, bone formation markers like ALP remain high in hyperthyroid patients during the treatment. In the light of this data, it is possible to conclude that osteoblastic activity lasts longer in hyperthyroidism. On the other hand, we demonstrated that these bone formation and resorption markers do not seem to be different in hypothyroid patients, even during the treatment, compared to the euthyroid controls.

[Quantitative ultrasonic myocardial texture analysis of the diabetic heart]. / Diyabet kalbinin kantitatif ultrasonik miyokard dokusu analizi.

OBJECTIVE: Contraction and relaxation of the heart cause decrease and increase in myocardial video intensity (MVI) recorded from echocardiographic images, respectively. The present study was planned to compare this physiological cyclic variations of MVI in patients with type 1 diabetes mellitus and healthy subjects. METHODS: For this purpose, standard echocardiographic examination was performed to 18 young patients (age 23.2+6.4; range: 15-37 years) with insulin dependent type 1 diabetes mellitus (diabetes duration: 7.8+5.6; range: 1-17 years) and 14 age and sex matched controls. In all subjects, end-diastolic and end-systolic 2D echocardiographic images of 3 consecutive beats that had been recorded on videotapes were digitized. The quantitative analysis of digitized imaging was performed with the help of a calibrated digitization system in order to calculate the septum and the posterior wall textural parameters. The cyclic variation index (CVI) of the mean gray level (MGL) was calculated according the formula: (MGL dias- MGL diast x 100. RESULTS: Among the groups, left ventricular diastolic dimension-index, fractional shortening, E/A ratio, and isovolumic relaxation time showed no statistically significant differences, while septum and (8.3+1.1 vs. 7.3+0.9 mm; p=0.016) and posterior wall thickness (8+0.6 vs. 6.8+1.1mm; p=0.004) and E-deceleration time (167+23 vs. 140=19 msec.; p=0.003) were significantly higher in diabetics. The diabetic patients showed significantly lower CVI both for septum (18.2+11.5% vs. 39.3+11.5%; p=0.0001) and posterior wall (16.4+16% vs. 40.5+9.2%; p=0.0001), respectively. CONCLUSIONS: Altered videoensitometric parameters possibly represent a preclinical alteration, conceivably related to the myocardial collagen content increase, which does not necessarily indicate an actual disease but may be considered an early marker of the histopathologic findings of diabetic cardiomyopathy.